Psoriasis is a common chronic relapsing inflammatory skin disease which affects 1-3% of the population. It is characterised by the circumscribed scaling erythematous plaques of various sizes and forms which in some cases may extend to more than 50% of the skin area. The psoriatic condition is composed of two main processes: cellular hyperproliferation and inflammation. Despite extensive research the etiology of the disease is still unknown.
Psoriasis is currently treated by a number of methods which include topical applications consisting of tar derivatives, steroids, vitamin D and its derivatives or vitamin A and its derivatives (J. P. Callen, Drug Therapy, April 1987, pp. 29-35). These therapies are only partially successful and may be accompanied by undesired side affects. Thus although steroids can be very effective, they are also frequently associated with side effects. Other therapies include phototherapy with or without concomitant systemic administration of psoralen derivatives. Additionally, systemic administration of steroids, methotrexate and cyclosporine have been used for treatment of severe cases of psoriasis. All of these therapies are associated with side effects. There is thus an urgent need for new effective, non-toxic therapeutics for psoriasis.
Atopic dermatitis is a chronic skin condition of unknown etiology, and which may be continuous from infancy to adulthood. There is about 4% incidence of atopic dermatitis from birth to 7 years (Halpern et al., J. Allergy Clin. Immunol. 51:139-151 (1973). In childhood, it is characterized by papules, erythema, thickening and lichenification. In the adolescent, the main symptoms are thickening and lichenification with erythema and scaling. Pruritis is a general feature of the disease. Systemic therapy includes antihistamine drugs and steroids, but the latter are reserved for unmanageable cases and used for the shortest period possible. Topical therapy includes fluorinated and fluorochlorinated corticosteroid preparations, but striae and cataracts are likely complications. Clearly there is as yet no satisfactory and safe drug treatment for atopic dermatitis.
Xanthine derivatives have been proposed for the treatment of psoriasis and atopic dermatitis. U.S. Pat. No. 4,141,976 proposes certain pharmaceutical preparations for the topical treatment of psoriasis. Among the compounds described are certain substituted alkylxanthine derivatives and substituted thioxanthines. However data demonstrating effectiveness is shown only for RO 20-1724 (d,1-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone, which is not a xanthine derivative. There is no data showing that the xanthine derivatives are effective therapeutics when topically administered to patients suffering from proliferative skin disease.
WO 9101730 describes the use of certain xanthine derivatives for the treatment of asthma, urticaria, eczema and rhinitis. Suggested modes of administration are listed as oral, rectal, topical, parenteral, intravenous, or intramuscular or through the respiratory tract. EP 195,496 describes the use of certain xanthine derivatives for treating proliferative skin disease such as psoriasis. The xanthine derivatives are administered orally. U.S. Pat. No. 4,716,165 describes the use of certain theobromine derivatives for treating asthma, allergic rhinitis, atopic dermatitis or eczema. WO 8905145 describes the use of certain xanthine derivatives for the treatment of a wide variety of disease states including psoriasis. EP 260,127 describes the oral administration of certain xanthine derivatives for the treatment of proliferative skin disease. U.S. 4,341,783 describes the use of topical dyphylline for the treatment of psoriasis. There is no teaching or suggestion in any of the above-listed patents and patent applications that the topical administration of the compounds of the instant invention would be more effective in the treatment of psoriasis or atopic dermatitis than the topical application of other xanthine derivatives described in the above-cited patents and patent applications.
Ravid et al. (Ravid et al., J. Allergy Clin. Immunol. 86:881-885 (1990) and J. Clin. Endocrinol. Metab. 70:1687-1692 (1990)) have shown that certain compounds which increase the levels of cyclic adenosine monophosphate (cAMP) are capable of inhibiting the mitogenic induced proliferation of peripheral blood mononuclear cells (PBMC) from both healthy and atopic patients. The only xanthine derivative tested in these articles was isobutylmethylxanthine (IBMX). However, there is no teaching or suggestion in these publications that other xanthine derivatives may have different or superior properties to IBMX. There is certainly no mention of pentoxifylline (PTX), propentofylline (PPF) or torbafylline (TBF).
Pentoxifylline (PTX) (3,7-dimethyl-1-(5-oxohexyl)-xanthine), propentofylline (PPF) (3-methyl-7-propyl-1-(5-oxohexyl)-xanthine) and torbafylline (TBF) (3-methyl-7-ethoxymethyl-1-(5-hydroxy-5-methylhexyl)-xanthine are related methyl-xanthine derivatives which are well known in the art for treatment of a variety of disease states. PTX is widely used systemically for the treatment of peripheral vascular diseases. PTX and PPF have been administered systemically for the treatment of senile dementia while systemic administration of TBF is under investigation for treatment of senile dementia, peripheral vascular disease and myopathy.
PTX has been used systemically for the treatment of various cutaneous lesions associated with or due to impaired or deficient blood flow in the dermis layer of skin and its effectiveness in the treatment of peripheral vascular diseases is described by H. Ely, Dermatologic Clinics 6:585-608 (1988). There is no teaching that PTX, or any of its congeners, PPF or TBF, were effective in the treatment of psoriasis or atopic dermatitis, which are lesions of the epidermis layer of the skin rather than one of the peripheral blood vessels.